Multiple sclerosis (MS) is a chronic, inflammatory disease that affects the central nervous system (CNS). MS can cause a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, and pain. Although many patients lead full and rewarding lives, MS can cause impaired mobility and disability in more severe cases.
Multiple sclerosis affects neurons, the cells of the brain and spinal cord that carry information, create thought and perception, and allow the brain to control the body. Surrounding and protecting some of these neurons is a fatty layer known as the myelin sheath, which helps neurons carry electrical signals. MS causes gradual destruction of myelin (demyelination) and transection of neuron axons in patches throughout the brain and spinal cord. The name multiple sclerosis refers to the multiple scars (or scleroses) on the myelin sheaths. This scarring causes symptoms which vary widely depending upon which signals are interrupted. It is thought that MS results from attacks by an individual's immune system on the nervous system and is therefore categorized as an autoimmune disease.
MS currently does not have a cure, though several treatments are available which may slow the appearance of new symptoms. Interferon-beta (IFNβ), a type-I Interferon, is a pleiotropic cytokine with immunomodulatory properties and has become a global standard in the treatment of MS. Despite the well documented efficacy in responders to this medication, a substantial number of patients fail to respond to IFNβ. Why IFNβ therapy is or is not effective with respect to MS, and how IFNβ alters the clinical course of MS remains unclear. Putative mechanisms of action include the inhibition of T cell proliferation, regulation of a large number of cytokines, and blocking of blood-brain barrier opening via interference with cell adhesion, migration and matrix metalloproteinase activity.
Furthermore, unfortunately, many multiple sclerosis patients treated with IFNβ develop anti-IFNβ antibodies, which can interfere with the bioactivity of the injected cytokine. These neutralizing antibodies (NAB) prevent IFNβ from binding to its receptor, thereby blocking all the biological effects of IFNβ. This phenomenon is called “antibody-mediated decreased bioactivity (ADB)”. The incidence and titers of neutralizing antibodies that develop to IFNβ vary by the preparation of IFNβ used (IFNβ-1b and IFNβ-1a). Other factors that may influence the induction of NAB to IFNβ include the dose, frequency of administration, route of administration and treatment duration.
At present, two major types of assays are used to detect NAB to IFNβs: a) binding assays, which measure the ability of neutralizing antibodies in a patients' sera to bind to IFNβ, and b) neutralization assays (or bioassays), which measure the ability of patients' sera to neutralize the biologic effects of IFNβ.
An example of such neutralizing assay is the myxovirus resistance protein A (MxA) assay. This assay is based on evidence that type 1 IFNs selectively induce the Mx1 gene in human cells in a dose-dependent manner. The assay is based on detection using real-time RT PCR of gene expression of MxA to determine the in vivo biological effect of administered IFNβ. The Mx1 gene is expressed at very low levels before and relatively high levels after IFNβ treatment. The assay consists of taking a blood sample of a patient before and after injection within a few hours of the patient with a dose of IFNβ. Peripheral blood mononuclear cells are then collected and PCR is used to determine the level of MxA mRNA in the sample. When IFNβ binds and activates its receptor, the level of MxA RNA should be substantially increased in the postdose sample compared with the predose sample. If MxA RNA is not induced, this indicates that the injected IFN was unable to activate its receptor.
MxA assays may also be applied to evaluate IFNα bioavailability in patients suffering from hepatitis C (HCV) and/or hepatitis B (HBV) and treated with different IFNα regimes.
However, assays used to detect NAB in general differ in their sensitivity and specificity, and there can be high variability between laboratories in how these assays are performed. In addition, the above-described MxA assay in particular has the drawback that the assay is not patient-friendly. The assay requires the presence of a patient for donating a predose and postdose blood sample.
It is therefore an aim of the present invention to provide an improved method for monitoring the in vivo response of an individual to a treatment with a type I interferon (type I IFN), which overcomes at least some of the above-mentioned drawbacks of known methods.
More in particular, it is an aim of the invention to provide an in vitro method for monitoring the in vivo response of an individual to a treatment with a type I interferon.
The present invention also aims to provide an improved method for monitoring the development and/or occurrence of neutralizing antibodies in the course of a treatment with a type I interferon. More in particular, the present inventions aims to provide an improved in vitro method for evaluating the in vivo presence of antibodies directed against a type I interferon in an individual that is under treatment with said type I interferon.